Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers

• Published in: Life (Basel, Switzerland) Vol. 10; no. 11; p. 265
• Main Authors: Garrido-Navas, M Carmen, Tippins, Frances, Barwell, Julian, Hoffman, Jonathan, Codd, Veryan, Royle, Nicola J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 31.10.2020; MDPI AG
• Subjects: DNA mismatch repair; Lynch syndrome; MLH1; MSH2; telomeres; MSH2; MLH1; DNA mismatch repair; telomeres; Lynch syndrome
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life10110265

Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in carriers compared to carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither or children had consistently shorter or longer telomeres than their MMR parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with mutations, had significantly longer XpYp telomeres than their MMR parent. Altogether our data suggest that MMR insufficiency, particularly in carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.